Induction of immunosuppressive molecules and regulatory T cells counteracts the antitumor effect of interleukin-12-based gene therapy in a transgenic mouse model of liver cancer

Background/Aims: Hepatocellular carcinoma (HCC) often lacks curative treatment; therefore new efficient therapies are needed. In this work we aimed at evaluating the antitumor effect of interleukin-12 (IL-12)-based gene therapy on HCC occurring spontaneously in mice. Methods: A plasmid-vector expressing IL-12 in a liver-specific and doxycycline (Dox)-inducible manner was transferred by hydrodynamic injection to the liver of L-PK/c-myc mice with HCC. IL-12 expression was induced by administering Dox (3 cycles of I month duration separated by 1 month rest). Results: Dox administration increased serum IL-12 and IFN-gamma and induced tumor lymphocytic infiltration in all treated mice which was accompanied by tumor stabilization or regression in 40% of animals. The antitumor effect did not correlate with levels of IL-12 or IFN-gamma, nor with the intensity of tumor mononuclear infiltration. However, tumors from non-responder mice showed more abundance of Foxp3+ regulatory T cells and higher expression of the immunosuppressive molecules PD-1, PD-L1, VEGF, CTLA-4, IDO, and IL-10 than those that responded to therapy. Conclusions: Although long-term induction of IL-12 expression in the liver can inhibit HCC growth, the efficacy of the treatment appears to be limited by the activation of immunosuppressive mechanisms. (c) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.